Process for the production of 16,17-[(cyclohexylmethylen)bis(oxy)]-11,21-dihydroxy-pregna-1,4-dien-3,20-dion or its 21-isobutyrat by transketalisation

ABSTRACT

The invention relates to a process for the preparation of 16,17-[(cyclohexylmethylene)bis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-dione[11β,16α(R)] and similar compounds, by reaction of an appropriate 16,17-ketal with cyclohexanealdehyde.

This application was filed under 35 U.S.C. 371 as a national stage ofPCT/EP01/12808, filed Nov. 6, 2001.

TECHNICAL FIELD

The invention relates to a novel process for the preparation of a knownglucocorticoid, which is used in the pharmaceutical industry for theproduction of medicaments.

PRIOR ART

The international patent application WO 9422899 describes novelprednisolone derivatives and a process for their preparation. In thisprocess, 16-hydroxyprednisolone is reacted with cyclohexanealdehyde.German patent application DE 41 29 535 discloses novel glucocorticoidsand a process for their preparation. The process comprises reactingpregna-1,4-diene-3,20-dione-16,17-dihydroxy compounds, in the form oftheir 16,17-diester derivatives, with aldehydes (e.g. withcyclohexanealdehyde) to give the desired final products.

DESCRIPTION OF THE INVENTION

The invention relates to a process for the preparation of the compoundsof the formula 1,

in which

-   R is hydrogen (H) or isobutyryl [CO—CH(CH₃)₂], in predominantly    epimerically pure form.

It has now been found that the compounds of the formula 1 are obtainedin a simple manner in good yield and surprisingly high epimeric puritywhen, rather than the 16,17-dihydroxy compound or the 16,17-diester, thecorresponding 16,17-ketal, in particular the 16,17-acetonide derivative,is used as a starting material.

The invention thus relates to a process for the preparation of thecompounds of the formula 1 in predominantly epimerically pure form,which comprises reacting compounds of the formula 2,

in which

-   R is hydrogen (H) or isobutyryl [CO—CH(CH₃)₂],-   R1 is 1-4C-alkyl and-   R2 is 1-4C-alkyl,-   with cyclohexanealdehyde.

Preferably, the process is carried out using those compounds of theformula 2 in which R1 and R2 are in each case methyl (CH₃).

The reaction is carried out in suitable solvents such as, for example,ethers, e.g. dioxane, diisopropyl ether, esters, e.g. ethyl acetate,halogenated hydrocarbons, e.g. methylene chloride, chloroform, nitratedhydrocarbons, e.g. nitromethane, 2-nitropropane or preferably1-nitropropane, or without solvents, with addition of catalytic or elserelatively large amounts of acid, such as mineral acids, e.g.tetrafluoroboric acid or in particular perchloric acid, or sulfonicacids, in particular methanesulfonic acid, at temperatures ofadvantageously 0° C. to 60° C.

The reaction of the 16-hydroxyprednisolone ketal of the formula 2 withcyclohexanealdehyde normally yields an epimer mixture. Surprisingly, thereaction, however, is controlled according to the invention by means ofsuitable reaction conditions such that the R-epimer desired andindicated in formula 1 results. According to the invention, “inpredominantly epimerically puree form” thus means that the R-epimer(based on the absolute configuration at C-22) in the compound 1 whereR=hydrogen (H) results to at least 90%, preferably at least 95%, inparticular at least 97%, based on the total yield.

For the predominant preparation of the R-epimer, the followingconditions, for example, are preferred: as solvents, halogenatedhydrocarbons (such as methylene chloride or chloroform) or nitratedhydrocarbons (such as nitromethane, 2-nitropropane or preferably1-nitropropane) and, as a catalyst, methanesulfonic acid (attemperatures from 10° C. to 40° C.) or 35-70% strength, in particular60-70% strength, perchloric acid (at temperatures from 0° C. to 40° C.,preferably 15° C. to 30° C., in particular 20° C. to 25° C.).

If the R-epimer is desired in purer form than is achievable on accountof the reaction conditions, suitable separation and purificationsteps—such as, for example, preparative HPLC, or fractionalcrystallization such as described in international patent application WO9809982—may follow the reaction.

The following example serves to illustrate the invention in greaterdetail:

EXAMPLE16,17-[(Cyclohexylmethylene)bis(oxy)]-11,21-dihydroxypregna-1,4diene-3,20-dione[11β,16α(R)]

20 g of desonide are suspended in 70 ml of 1-nitropropane and treatedslowly with ice-cooling with 12.6 ml of 70% strength perchloric acid and6.6 g of cyclohexanealdehyde. The reaction mixture is stirred overnightat room temperature and then filtered. The filter cake is dissolved in90 ml of DMF and the solution is added dropwise with stirring to sodiumhydrogencarbonate solution. The precipitate is filtered off withsuction, washed with water and dried. 19 g of the title compound havingan R-/S-epimer ratio of 97.8/2.2 are obtained.

1. A process for the preparation of a compound of the formula 1

in which R is hydrogen (H), in over 95% epimerically pure form, whereincompounds of the formula 2

in which R is hydrogen (H), R1 is methyl (CH3) and R2 is methyl (CH3),are reacted with cyclohexanealdehyde using perchloric acid as a catalystand a nitrated hydrocarbon as a solvent at a temperature between 0° C.and 40° C.
 2. The process as claimed in claim 1, wherein the solvent isnitromethane, 2-nitropropane or 1-nitropropane.
 3. The process accordingto claim 1, wherein the solvent is 1-nitropropane.
 4. The processaccording to claim 1, wherein the perchloric acid is 60% to 70% instrength.
 5. The process according to claim 1, wherein the compound ofthe formula 1 is16,17-[(Cyclohexylmethylene)bis(oxy)]-11,21-dihydroxypregna-1,4-diene-3,20-diene[11β,16α(R)].